Patients suffering from chronic HF manifest an elevation of left ventricular end-diastolic pressure and frequently volume, according to the well-known heterometric autoregulation principles espoused by Frank and Starling. This may also occur while left ventricular end-diastolic volume remains normal due to a decrease in left ventricular compliance concomitant with increased ventricular wall stiffness. HF due to chronic hypertension, ischemia, infarct or idiopathic cardiomyopathy is associated with compromised systolic and diastolic function involving decreased atrial and ventricular muscle compliance. These may be conditions associated with chronic disease processes or complications from cardiac surgery with or without specific disease processes. Most heart failure patients do not normally suffer from a defect in the conduction system leading to ventricular bradycardia, but rather suffer from symptoms which may include a general weakening of the contractile function of the cardiac muscle, attendant enlargement thereof, impaired myocardial relaxation and depressed ventricular filling characteristics in the diastolic phase following contraction. Pulmonary edema, shortness of breath, and disruption in systemic blood pressure are associated with acute exacerbations of heart failure. All these disease processes lead to insufficient cardiac output to sustain mild or moderate levels of exercise and proper function of other body organs, and progressive worsening eventually results in cardiogenic shock, arrhythmias, electromechanical dissociation, and death.
Such patients are normally treated with drug therapies, including digitalis, which may lead to toxicity or lose effectiveness over time. Many inotropic drugs have recently become available, targeted at various receptors in the myocyte and designed for the purpose of directly stimulating cardiac tissue in order to increase contractility. However, there exist many possible undesirable side effects, in addition to the fact that these drugs do not always work for their intended purpose. This is especially characteristic of the patient suffering from end-stage heart failure.
In the early days of implantable cardiac pacing, it was observed that paired pacing (two or more closely spaced pacing pulses delivered at the time-out of an escape interval) and triggered or coupled pacing (one or more pacing pulses delivered following the detection of a P-wave or R-wave terminating an escape interval) with relatively short interpulse intervals (150 to 250 milliseconds in dogs and about 300 milliseconds in human subjects) beneficially slowed heart rate and increased cardiac output. The result of the second pulse, applied shortly following the refractory period of the first paced or spontaneous depolarization, is to further prolong ventricular refractoriness and effect a slowing of the heart rate from its spontaneous rhythm. This slowing effect has been employed since that time in many applications, including the treatment of atrial and ventricular tachycardias, where a single pulse or a burst of pulses are coupled to a spontaneous tachycardia event with a coupling interval that is shorter than and can be set as a fraction of the tachycardia interval as taught, for example, in U.S. Pat. Nos. 3,857,399 and 3,939,844. The slowing of the heart rate by coupled pacing is accompanied by the ability to increase or decrease the rate with subsequent coupled pacing within wide limits.
Paired and coupled stimulation of a heart chamber also cause a potentiation of contractile force effect through a phenomenon known as post-extrasystolic potentiation (“PESP”) described in detail in commonly assigned U.S. Pat. No. 5,213,098. The force of contraction of the heart is increased during the following heart cycle that the paired or coupled stimulation is applied, and the increase persists but gradually diminishes over a number of succeeding heart cycles. Other measurable effects that also persist but gradually decline over a number of heart cycles include changes in the peak systolic blood pressure, the rate of contraction of the ventricular muscle with a resulting increase of the rate of rise of intraventricular pressure (dP/dt), an increase in coronary blood flow, and an increase in the oxygen uptake of the heart per beat. Investigators observed that potentiation therapy was accompanied by an increase in the myocardial oxygen consumption of 35% to 70% as compared with single pulse stimulation at the same rate and was associated with a significant improvement in ejection fraction. The addition of a third stimulus increased the myocardial oxygen uptake even further without any attendant observed increase in cardiac contractile force. The alterations in coronary flow roughly parallel the oxygen consumption of the heart as observed in such studies.
The marked potentiation effect produced by paired stimulation led certain investigators to speculate that PESP stimulation would be beneficial in treating heart failure in humans and conducted studies using the technique in the treatment of acute heart failure induced in canine subjects. Improvements in left ventricular performance and cardiac output produced by such paired pacing in these canines was observed by several investigators. In other studies conducted on relatively normal dogs' hearts, it was confirmed that paired pacing offered no increase in cardiac output, most likely due to reflex compensation. Early investigators conducted a large number of animal and human studies employing paired and coupled stimulation of the atrial and ventricular chambers, and medical devices were made available by Medtronic, Inc. and other companies in an effort to employ potentiation. However, it was realized that the application of closely timed paired and coupled pacing pulses, particularly the high energy pacing pulses that were employed at that time in implantable pacemakers, could trigger a tachyarrhythmia in patient's hearts that were susceptible. The efforts to capitalize on the PESP effects were largely abandoned. A history of the investigations and studies conducted is set forth in the above-referenced '098 patent.
Since dual chamber pacing was developed, conventional, atrioventricular (AV) synchronous pacing systems, including DDD and DDDR pacing systems, marketed by Medtronic, Inc. and other companies, have also been prescribed for treatment of HF as well as a variety of bradycardia conditions. Certain patient groups suffering heart failure symptoms with or without bradycardia tend to do much better hemodynamically with AV synchronous pacing due to the added contribution of atrial contraction to ventricular filling and subsequent contraction. However, fixed or physiologic sensor driven rate responsive pacing in such patients does not always lead to improvement in cardiac output and alleviation of the symptoms attendant to such disease processes because it is difficult to assess the degree of compromise of cardiac output caused by HF and to determine the pacing parameters that are optimal for maximizing cardiac output. Selection of an optimal AV delay often requires obtaining pressure data involving an extensive patient work-up as set forth in commonly assigned U.S. Pat. No. 5,626,623.
The above-referenced '098 patent discloses PESP cardiac pacing energy stimulator for applying paired and/or triggered pacing stimulation pulses to the right atrium and/or ventricle incorporating one or more sensors and signal processing circuitry for controlling the frequency of or number of heart cycles between periodic delivery of triggered or paired pacing to induce and optimize the PESP effect for the treatment of HF or other cardiac dysfunctions. A first sensor, e.g., a ventricular or arterial blood pressure or flow sensor, is employed to monitor the performance of the heart and to develop a cardiac performance index (CPI). A second sensor, e.g., an oxygen saturation sensor positioned in the coronary sinus, is employed to monitor cardiac muscle stress and develop a cardiac stress index (CSI) to balance performance and stress. The disclosed PESP stimulator may be incorporated into a dual chamber (DDD) pacing system with or without physiologic rate control and with or without backup cardioversion/defibrillation therapy capabilities or in a separate, single purpose device. The PESP stimulator has particular application in atrial stimulation for augmenting filling of the ventricles.
A series of PCT publications including, for example, PCT WO 97/25098 describe the application of one or more “non-excitatory” anodal or cathodal stimulation pulses to the heart and maintain that improvements in LV performance may be realized without capturing the heart. In a further commonly assigned U.S. Pat. No. 5,800,464, sub-threshold anodal stimulation is provided to the heart to condition the heart to mechanically respond more vigorously to the conventional cathodal supra-threshold pacing pulses.
Thus, various stimulation regimens have been proposed for the treatment of cardiac dysfunction including HF which involve application of supra-threshold and/or sub-threshold stimulation paired or coupled pacing pulses or pulse trains. Moreover, various electrodes have been proposed for single site and multi-site delivery of the stimulation pulses to one or more heart chamber in the above-referenced patents and publications. However, it remains difficult to economically determine appropriate candidates that would benefit from such stimulation and to measure the efficacy of a given stimulation regimen and/or electrode array. Extensive catheterization procedures must be conducted of a heart failure patient to determine if he or she is a candidate for implantation of such a system. Then, the efficacy of any given treatment must be assessed at implantation and in periodic post-implant follow-up clinical tests. The patient work-up and follow-up testing must take into account or simulate known patient activities, patient posture, and whether the patient is awake or asleep in order to be representative of the heart failure condition over a daily time span. Furthermore, these therapies are susceptible to losing efficacy or causing arrhythmias with shifts in stimulation timing or the physiologic response to stimulation.
Physiologic and device operating data gathering capabilities have been included in modern implantable cardiac pacemakers and implantable cardioverter/defibrillators (ICDs) in order to provide a record of bradycardia or tachyarrhythmia episodes and the response to same provided by the pacemaker or ICD. The stored physiologic device operations and patient data as well as real-time electrogram (EGM) data can be uplink telemetered to an external programmer for display and analysis by medical heath care providers, as is well known in the art.
In addition, implantable cardiac monitors have been clinically used or proposed for use for monitoring hemodynamic and electrical signals of a patient's heart that do not presently include any stimulation capabilities, e.g., cardiac pacing or cardioversion/defibrillation. Such implantable monitors are implanted in patients to develop data over a longer time period than in the clinical setting that can be retrieved in the same manner and used to diagnose a cardiac dysfunction, including HF, that manifests itself sporadically or under certain loads and stresses of daily living.
One such implantable EGM monitor for recording the cardiac electrogram from electrodes remote from the heart as disclosed in commonly assigned U.S. Pat. No. 5,331,966 and PCT publication WO 98/02209 is embodied in the Medtronic® REVEAL® Insertable Loop Recorder having spaced housing EGM electrodes. More elaborate implantable hemodynamic monitors (IHMs) for recording the EGM from electrodes placed in or about the heart and other physiologic sensor derived signals, e.g., one or more of blood pressure, blood gases, temperature, electrical impedance of the heart and/or chest, and patient activity have also been proposed. The Medtronic® CHRONICLE® IHM is an example of such a monitor that is coupled through a lead of the type described in commonly assigned U.S. Pat. No. 5,564,434 having capacitive blood pressure and temperature sensors as well as EGM sense electrodes. Such implantable monitors when implanted in patients suffering from cardiac arrhythmias or heart failure accumulate date and time stamped data that can be of use in determining the condition of the heart over an extended period of time and while the patient is engaged in daily activities.
A HF monitor/stimulator is disclosed in commonly assigned U.S. Pat. No. 6,104,949 that senses the trans-thoracic impedance as well as patient posture and provides a record of same to diagnose and assess the degree and progression of HF. The sensed trans-thoracic impedance is dependent on the blood or fluid content of the lungs and assists in the detection and quantification of pulmonary edema symptomatic of HF. Trans-thoracic impedance is affected by posture, i.e. whether the subject is lying down or standing up, and the sensed trans-thoracic impedance is correlated to the output of the patient posture detector to make a determination of presence of and the degree of pulmonary edema for therapy delivery and/or physiologic data storage decisions.
A monitor/stimulator is disclosed in U.S. Pat. No. 5,417,717, that monitors and assesses the level of cardiac function then permits a physician to arbitrate the therapy mode, if therapy is indicated. The monitor/stimulator assesses impedance, EGM, and/or pressure measurements, and then calculates various cardiac parameters. The results of these calculations determine the mode of therapy to be chosen. Therapy may be administered by the device itself or a control signal may be telemetered to various peripheral devices aimed at enhancing the heart's function. Alternatively, the device may be programmed to monitor and either store or telemeter information without delivering therapy.
Particularly, the implantable monitor/stimulator monitors conventional parameters of cardiac function and contractile state, including all phases of the cardiac cycle. Thus, assessments of contractile state measured include indices of both cardiac relaxation and contraction. Utilizing the dual source ventricular impedance plethysmography technique described in U.S. Pat. No. 4,674,518, the monitor/stimulator monitors cardiac function by assessing hemodynamic changes in ventricular filling and ejection or by calculating isovolumic phase indices by known algorithms. The primary calculations involve: (1) the time rate of change in pressure or volume, dP/dt or dV/dt, as isovolumic indicators of contractility; (2) ejection fraction as an ejection phase index of cardiac function according to the known quotient of stroke volume divided by end diastolic volume; (3) Maximal elastance, EM; (4) regression slope through maximal pressure-volume points as a further ejection phase index of contractility using the method of Sagawa; (5) stroke work according to the known pressure-volume integration; (6) the time course of minimum (end) diastolic pressure-volume measurements according to the method of Glantz as a measure of diastolic function; and (7) cardiac output calculation according to the known product of heart rate and stroke volume as an index of level of global function.
While measurement and storage of this group of parameters of cardiac function and contractile state can provide valuable information about the state of heart failure, there are other parameters that of even greater value. Momentary changes to a patient's autonomic state can change blood pressure (P), heart rate, and pressure rate of change (dP/dt) contractility measures and not be reflective of a “true” functional state change of the heart. Such momentary changes in autonomic state are caused by excitement and postural changes as noted in the above-referenced '949 patent and other movements, such as bending down to pick up an object or suddenly standing up from a sitting or reclining position. It would be desirable to obtain cardiac data that provides an enhanced assessment of cardiac contractile dysfunction state (rather than a measure of pulmonary edema as in the '949 patent) that are less sensitive to such patient mental states, movements and posture changes by enhanced signal processing of relatively simple to measure cardiac signals and states.
In a related patent disclosure identified as U.S. patent application Ser. No. 09/750,631 filed 28 Dec. 2000 by Deno et al. ('631 disclosure) (WO 02/053026 A2, published 11 Jul. 2002) of common ownership and having the same caption as the present disclosure, a variety of techniques for providing heart failure therapy were described. The following subject matter represents some of the apparatus (including diverse sensors) and techniques for providing PESP therapy as described in the '631 disclosure, which is hereby incorporated by reference into the present disclosure. In accordance with '631 disclosure, an implantable stimulator and monitor measures a group of parameters indicative of the state of heart failure employing EGM signals, measures of blood pressure including absolute pressure P, developed pressure DP (DP=systolic P−diastolic P), and/or dP/dt, and measures of heart chamber volume (V) over one or more cardiac cycles. These parameters include: (1) relaxation or contraction time constant (tau); (2) mechanical restitution (MR), i.e., the mechanical response of a heart chamber to premature stimuli applied to the heart chamber; (3) recirculation fraction (RF), i.e., the rate of decay of PESP effects over a series of heart cycles; and (4) end systolic elastance (EES), i.e., the ratios of end systolic blood pressure P to volume V. These cardiac state parameters are determined periodically regardless of mental state, patient posture and activity level. However, certain of the parameters are only measured or certain of the data are only stored when the patient heart rate is regular and within a normal sinus range between programmed lower and upper heart rates.
The implantable stimulator and monitor is operated in one or more of the measurement modes that, in some instances, require delivery of an extrasystolic (ES) pulse after an extrasystolic interval (ESI) to induce PESP effects that are measured. In the present invention, the PESP capability is also employed to strengthen the cardiac contraction when one or more of the MR, RF, tau, and EES parameters show that the heart condition has progressed to benefit from increased contractility, decreased relaxation time, and increased cardiac output. In this context, the stimulation therapy is referred to as PESP stimulation or PESP pacing. In accordance with the invention, the effects of the applied PESP stimulation therapy can be observed over time by entering a heart function parameter measuring mode and gathering the parameter data.
Preferably, the parameter data is associated with a date and time stamp and with other patient data, e.g., patient activity level, and the associated parameter data is stored in implantable medical device (IMD) memory for retrieval at a later date employing conventional telemetry systems. Incremental changes in the parameter data over time, taking any associated time of day and patient data into account, provide a measure of the degree of change in the condition of the heart.
The '631 disclosure combines these approaches, rendering a device that detects and monitors levels of cardiac function and delivers or modifies a therapy on the basis of this monitored information. The primary mode of delivery is direct electrical stimulation, resulting in improved contractility, relaxation, pressures or cardiac output. The implantable stimulator and monitor that is capable of performing these functions comprises an implantable pulse generator (IPG) and lead system extending into operative relation with at least one and preferably multiple heart chambers for electrical sensing and stimulation, blood pressure measurement and chamber volumetric measurement during contraction and relaxation. The IPG has a sense amplifier for each heart chamber of interest that is coupled through a lead conductor with electrical stimulation/sense electrodes for sensing cardiac electrical heart signals originating in or traversing that heart chamber so that the sense amplifier can detect a P-wave in an atrial chamber or R-wave in a ventricular chamber. The IPG has timing circuitry for timing out atrial and/or ventricular escape intervals and the ESI of coupled or paired PESP stimulating pulse(s). The IPG has a pulse generator coupled with at least one stimulation/sense electrode for delivering pacing pulses and PESP stimulation pulses to each heart chamber of interest. The IPG has blood pressure signal processing circuitry coupled through lead conductors with a blood pressure sensor located in a distal lead section in or in operative relation to each heart chamber of interest for deriving blood pressure, P, and dP/dt samples. The IPG also has volume determining circuitry coupled with a volumetric sensor located in or in relation with each heart chamber of interest for deriving a signal representative of heart chamber volume, V. The volumetric sensor preferably comprises a set of impedance sense electrodes located along a single impedance lead or on a plurality of impedance leads, and the volume determining circuitry coupled to the impedance sensor electrodes detects impedance between selected electrode pairs. The impedance sense electrodes are distributed about the heart chamber such that the distance between the separated electrodes and the measured impedance changes with contraction and relaxation of the heart chamber walls.
The implantable stimulator and monitor can be embodied into a single chamber, dual chamber or multi-chamber (bi-atrial and/or bi-ventricular) rate responsive pacemaker for providing bradycardia pacing when intrinsic sinus heart rate falls below a programmed lower HR. Or, the implantable stimulator and monitor can be embodied into an ICD including such single chamber, dual chamber or multi-chamber rate responsive pacing capabilities as well as tachyarrhythmia detection and cardioversion/defibrillation shock delivery capabilities. In either case, tachycardia detection and anti-tachycardia pacing as well as cardiac resynchronization pacing therapies can also be incorporated.
This summary of the '631 disclosure and the objects, advantages and features thereof have been presented here simply to point out some of the ways that the '631 provides for overcoming difficulties presented in the prior art and to distinguish the invention described in the '631 reference from the prior art and is not intended to operate in any manner as a limitation on the interpretation of claims that are presented initially in the patent application and that are ultimately granted.